This project is under the broad challenge area of 05: Comparative Effectiveness Research. The specific challenge topic is 05-AG-103, Imaging and Fluid Biomarkers for Early Diagnosis and Progression of Aging-related Diseases and Conditions including Neurodegenerative Diseases. Evidence suggests that the pathology of Alzheimer's disease (AD) begins to accrue as many as 10- 15 years prior to the earliest signs and symptoms of cognitive decline characteristic of AD. This period, during which pathology is developing but individuals remain cognitively normal, has been referred to as "pre-clinical AD". Given that neurodegeneration is present even at the earliest clinical stages of AD and that promising treatments could potentially delay the onset or prevent progression of AD, it will be important to have antecedent biomarkers that: predict with high likelihood the development of cognitive decline in individuals who are still cognitively normal but developing AD pathology. Using a combination of CSF biomarkers and both structural and amyloid imaging, we have found that CSF amyloid-[unreadable]42 (A[unreadable]42) and tau are useful biomarkers for both detecting A[unreadable] and tau deposition and for predicting progression from cognitively normal to very mild dementia. However, there is a great need for finding additional biomarkers that when used together are even stronger in predicting the prognosis in individuals who have preclinical AD. It is likely that unbiased biomarker discovery approaches utilized in combination with current biomarker and imaging techniques will provide additive predictive value. Using a new quantitative mass spectrometry technique termed targeted label free LC-MS/MS analysis, we have preliminary data showing that we can assess several thousand individual proteins accurately and quantitatively in individual CSF samples as well as differentiate subjects with very mild AD from controls by using unsupervised hierarchical clustering analyses. By applying this technique to our current large collection of CSF obtained from longitudinally followed research volunteers who have already been assessed clinically, neuropsychologically, with structural MRI and amyloid imaging, we hypothesize that we can distinguish novel patterns in the CSF proteome that will enhance our ability to diagnose the preclinical stage of AD, and identify subjects who will soon progress to dementia. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a major public health problem. The most effective therapies are likely going to be those that that are implemented before there is irreversible cell and synaptic loss. This means that there is a great need to identify antecedent biomarkers for AD so that therapies can be initiated as early as possible in the disease course to delay or even prevent the disease.